Ingestion of anitcoagulant rodenticides (ACRs) is one of the most common toxicities seen in veterinary medicine. The ACRs include those listed in table 1 below. It is important to note that not all rodenticides ingested are anticoagulant. Bromethalin, cholecalciferol, strychnine, and zinc phosphide are common rodenticides that do not work by altering the coagulation cascade and affecting hemostasis. As such, it is important to identify the active ingredient (not just the brand name) before assuming a rat poison's mechanism of action is anticoagulant in origin.
As Table 1 illustrates, there are numerous possible active ingredients in ACRs and thus it has been our experience at CCVS that in most cases of toxicity or ingestion, the actual amount ingested can be difficult to determine. Therefore, all ingestions are treated as though they are potentially toxic.
Mechanism of action
Anticoagulants are ingested and transported to the liver via chylomicrons and the portal vein. In the liver, Vitamin K1 is required for the production of functional clotting factors II, VII, IX, and X. Vitamin K1 hyrodquinone is converted to vitamin Vitamin K1 epoxide in the formation of these clotting factors. The Vitamin K1 epoxide is recycled back into Vitamin K1 hydroquinone by the enzyme Vitamin K1 epoxide reductase. It is this recycling enzyme that is inhibited by anticoagulant rodenticides. Thus ingestion of these toxins increases the body's requirement for vitamin K far beyond what can be ingested in the diet, leading to a relative shortage of vitamin K and the production of dysfunctional clotting factors II, VII, IX, and X.1
There are two distinct populations of pets presenting for rodenticide exposure, acute ingestion and symptomatic toxicity. We will discuss these individually as treatment is very different for these two populations.
Acute Ingestion
Pets presented for ingestion within the last several hours are classified as acute ingestion. They have no clinical signs of rodenticide toxicity but are suspected or known to have ingested the drug. The focus on treatment for pets with acute ingestion is decontamination. Emesis can be induced with apomorphine (0.03mg/kg IV, IM, or subconjuctival) or hydrogen peroxide (5mL/5 lbs by mouth, not to exceed 45mL per dog). Apomorphine is preferred as hydrogen peroxide may predispose to esophagitis. Activated charcoal with or without sorbitol (10mL/kg) can be given to prevent any further absorption in the gastrointestinal tract. Generally at CCVS we administer activated charcoal without sorbitol when treating patients as outpatients to prevent dehydration and hyperosmolality that can occur with activated charcoal use.
Traditionally, these patients are then treated with vitamin K1 (2.5 - 5mg/kg PO divided into twice daily doses). However, vitamin K1 has been reported to cause hemolysis in some patients and is not a benign medication. Although it may still be required in some cases, a recently published study indicates that we may not need to give vitamin K1 following acute ingestion. In this study, 115 dogs that had ingested rodenticide within 6 hours of presentation to the hospital were treated with decontamination and then rechecked in 2-6 days. A prothrombin time (PT) was checked on these dogs. Only 8.3% of them had a prolonged PT and were started on vitamin K1 at that time. No patients had any evidence of hemorrhage.2
If the decontamination efforts are successful, an alternative to administering pills for several weeks is to recheck a PT 48 hours after ingestion. The PT will prolong prior the onset of clinical bleeding and the activated partial thromboplastin time (aPTT) as factor VII has the shortest plasma half-life. If it is prolonged, vitamin K1 can be started at that time if the clinician knows exposure was indeed above toxic levels. If the PT is normal at the 48 hour recheck, no further therapy or rechecks are required. At CCVS, we employ this method along with a stern warning that failure to return for the recheck PT could result in death of the pet if bleeding occurs. We also perform the PT testing in-house to avoid delays that could lead to bleeding while awaiting results.
Clinical Toxicity
This patient population ingested an ACR some days prior to the onset of clinical signs unbeknownst to the owner. The diagnosis is made less on identifying what toxin was eaten than by confirming a coagulopathy in the face of active bleeding. Clincial signs of toxicity usually occur within 3-5 days of ingestion. They may include hematuria, hematemesis, epistaxis, hematomas, coughing, respiratory distress, or lethargy and depression. Hemorrhage can occur at any mucosal site or in the thoracic or abdominal cavities. A retrospective study reported that signs of internal hemorrhage are seen more commonly than external hemorrhage.3
Diagnosis is traditionally made by evaluation of the platelet count and clotting times. In a patient with evidence of hemorrhage, the platelet count may be decreased, but should not be below 50,000/mL. Spontaneous hemorrhage is not seen from thrombocytopenia until the count is less than 50,000/mL. The PT and aPTT will both be prolonged. Classically, the PT is more prolonged as factor VII has the shortest plasma half-life. In active hemorrhage, both the PT and aPTT may be significantly prolonged (often above the detectable range).
There are numerous reasons for patients to have mild thrombocytopenia and elevated PT and aPTT resulting in clinical hemorrhage including disseminated intravascular coagulation and hereditary coagulopathies. To confirm diagnosis of rodenticide toxicity, a rodenticide panel is available through the University of Pennsylvania Toxicology Laboratory as well as UC Davis+ Panels such as this can be helpful in confirming diagnosis of rodenticide toxicity, but will take several days for results to be available.
Treatment involves stabilizing the patient and supplying them with functional clotting factors. This is typically done with blood product transfusions. Fresh whole blood (20mL/kg) can be used to supply both red blood cells and clotting factors. Fresh frozen or frozen plasma (10mL/kg) can be used to supply clotting factors. Because a unit of Fresh frozen plasma becomes "frozen plasma" after a year, and frozen plasma is viable for another 2 years, plasma useful for anticoagulant rodenticide intoxication has shelf life of up to 3 years if stored frozen. This means plasma can be kept in stock at any veterinary hospital that will likely treat one bleeding anticoagulant rodenticide case in that time-frame. The patient should be transfused until the PT and aPTT are within normal limits and active hemorrhage has subsided. This means that patients may require multiple transfusions, typically at CCVS dogs require 10-20mL/kg of plasma to normalize the PT and aPTT but there have been cases that have required much more as well as red blood cells due to active bleeding and consumption of clotting factors.
Treatment specific to the bleeding organ may be required. Oxygen therapy is provided to animals with hemorrhage into the cervical tissues, mediastinum, pleural space, or lung parenchyma. Removal of blood in body cavities must be considered carefully. Thoraco- or abdominocentesis is generally avoided until plasma is given unless the patient is in danger of ventilatory failure. Intracranial hemorrhage leading to signs of intracranial hypertension can be treated with hypertonic saline (7-7.5% NaCl 4mL/kg IV over 30 minutes). Administration of mannitol is controversial as mannitol may leak into the area of hemorrhage and act to recruit additional fluid, worsening signs of intracranial hypertension.
Vitamin K1 therapy will be required in these patients for up to 30 days, but should not be used as the sole therapy because it takes 12-24 hours from the time of administration for the liver to produce functional clotting factors. In a patient with active hemorrhage, this will lead to prolonged bleeding for that length of time which could be life-threatening. With aggressive treatment, often employing the use of blood products, rodenticide toxicity usually carries a good prognosis. Although the hemorrhaging organ can affect prognosis with bleeding in the lungs and brain giving the clinician less time to control hemorrhage, a recent study showed overall survival to be 90% with 79% of patients discharged from the hospital within 48 hours.3
References
1 Murphy, MJ. Rodenticides. Vet Clin Small An 32 (2002): 469-484.
2 Pachtinger, GE, Otto, CM, Syring RS. Incidence of prolonged prothrombin time in dogs following gastrointestinal decontamination for acute anticoagulant rodenticide ingestion. JVECC. 2008. Vol 18 (3): 285-291.
3 Haines B. Anticoagulant rodenticide ingestion and toxicity: a retrospective study of 252 canine cases. Aust Vet Pract. June 2008; 38(2): 38-50.
Footnotes
+ http://www.vet.upenn.edu/FacultyandDepartments/Pathobiology/PathologyandToxicology/tabid/412/Default.aspx